The Clinical Psychopharmacology Section conducts preclinical and clinical research into the mechanisms of action of cocaine. A major component of this project, conducted in collaboration with investigators at NIDDK and NIMH, is the synthesis and evaluation of analogs of GBR12909 as putative cocaine antagonists or cocaine substitution-type medications. As part of this project, we synthesized and evaluated the first chiral "GBR" derivatives as potent and enantioselective inhibitors of dopamine reuptake. In an extension of previous studies, we showed that daily administration of GBR12909 suppresses cocaine self-administration in Rhesus monkeys without the development of tolerance, supporting its potential use in the treatment of cocaine addiction and that GBR12909 blocks the increase in extracellular DA produced by intravenous cocaine. Another component involves investigation of the possible heterogeneity of DA transporter binding sites. This project has identified multiple and novel binding sites for the high affinity cocaine analog, [125I]RTI-55. Another component of this project addresses the role of classical conditioning in cocaine-induced behavioral sensitization. These studies demonstrated that associative learning mechanisms are involved in the acquisition of context-specific behavioral sensitization to cocaine. Studies with genetically inbred strains of mice showed that the occurrence of sensitization is not correlated with either the potency or efficacy of cocaine as a motoric stimulant. Human studies failed to demonstrate cocaine-sensitization with a one day training paradigm (IRP-174). Open-label studies with phentermine and fenfluramine showed that these medications suppress cocaine craving in addicts seeking treatment. Clinical research protocols are in preparation to determine the efficacy of fenfluramine and phentermine as treatments for alcohol and cocaine addiction.